Sterol regulatory element-binding protein-1c (SREBP-1c) is a key transcription activator of lipogenic genes. Given the close association between dysregulation of lipid homeostasis and major human diseases, such as type 2 diabetes, understanding the regulation of SREBP-1c-dependent transcription will provide not only novel insights into the molecular control of the development of fatty liver and dyslipidemia but also potential therapeutic opportunities for fighting these diseases. At present, the pathways that regulate nuclear SREBP-1c activation and inactivation are poorly defined. Recent studies have demonstrated the NAD-dependent protein deacetylase SIRT1 as a negative regulator of SREBP-1c, suggesting that modulation of SIRT1 expression or enzymatic activity can affect lipid metabolism. The preliminary data have shown that the lysine-specific demethylase-1 (LSD1) is a critical regulator of SIRT1 and controls the expression of lipogenic genes. Surprisingly, a frequently used small molecule, which has known functions on lipid metabolism, displayed a novel function of inhibiting LSD1 activity. Thus, the central hypothesis of this proposal is that LSD1 activates SREBP-1c-mediated transcription and lipogenesis by repressing SIRT1. The following three Specific Aims are proposed to test this hypothesis: 1) Determine the role of LSD1 in regulating lipid metabolism in primary hepatocytes and mouse livers in vivo;2) Elucidate the molecular mechanisms of LSD1 regulation on SIRT1 in relevance to de novo lipogenesis;and 3) Target LSD1 for modulating SREBP-1c activity/level and de novo lipogenesis. A series of in vitro and in vivo experiments are proposed to determine the regulatory mechanisms and significance of the LSD1/SREBP pathway in lipid metabolism. The long-term objectives of this proposal are to determine the role of LSD1 in nutritional regulation of SREBP-1c function and in controlling lipid homeostasis in conditions of metabolic disorder. This application is not only significantly relevant to public health, but also highly innovative and will have major impacts to the field of lipid metabolism. Together, the proposed studies will address the molecular link between LSD1 and SREBP-1c in regulating lipid homeostasis and its potential role in the development of diseases with dysregulated lipid homeostasis, such as obesity, type 2 diabetes and cardiovascular diseases. PUBLIC HEALTH RELEVANCE: Aberrant hepatic lipogenesis causes fatty liver and dyslipidemia, which are closely linked to human diseases, including type 2 diabetes, obesity, and cardiovascular complications. The proposed research will study the mechanisms and functions of the histone demethylase LSD1 in regulating de novo lipogenesis. Thus, the outcomes of this project have the potential to guide the development of novel therapeutic approaches, and will have a significant impact on the treatment of human diseases with dysregulated lipid homeostasis.